The long-term goal of this proposal is to explore a possible role for the synaptic apoE receptor (LRP) in Alzheimer's disease (AD) pathogenesis and synaptic degeneration. Apolipoprotein E (apoE) has been implicated in degeneration and regeneration of the central nervous system (CNS) synapse, and has generated great interest since apoE4, one of three isoforms, was shown to greatly increase the risk of Alzheimer's disease. LRP is a receptor for multiple ligands, including apoE-enriched lipoproteins, alpha2-macroglobulin, and tissue-type plasminogen activator. However, the physiological role(s) of LRP in the CNS remain largely unknown. Our preliminary studies show that LRP is highly enriched in synaptic nerve terminals isolated from human cerebral cortex. This raises the possibility that LRP regulates lipoprotein metabolism and protease clearance at the synapse and that it may interact differentially with various apoE isoforms. In the proposed studies, we will determine the fine anatomical localization of LRP within the human cortical synaptic apparatus using immunoelectron microscopy, subcellular fractionation, and immuno-isolation of the LRP- containing organelles. LRP expression at the synapse of specific brain regions of AD and control individuals will be examined using specific LRP antibodies. Interaction of synaptic LRP with its multiple ligands in the brain, including AD-associated apoE4, will be determined by ligand blotting, affinity-crosslinking, and solid-phase binding assays. The data that will be generated in the proposed studies will provide new insight into the physiological functions of LRP in the regulation of apoE and protease metabolism at the synapse, emphasizing the basis of AD-associated synaptic pathology.